Behavior Of Female Offspring Research Articles

Impact of Mid and Late-gestation Toll-like Receptor 7 Stimulation on Development and Anxiety-like Behavior in Offspring

Maternal immune activation (MIA) can occur during pregnancy due to exposure to infectious diseases or other inflammatory conditions. MIA is a risk factor for various psychiatric disorders, such as major depressive disorder, as well as cardiac disorders in the offspring. Resiquimod (R-848), a toll-like receptor (TLR) 7 agonist, induces systemic inflammatory responses and mimics responses to viral infections. Previous studies have shown that MIA with a TLR 4 agonist lipopolysaccharide or the viral mimic, TLR 3 agonist polyinosinic:polycytidylic acid produces neuropsychiatric effects in the offspring. The current project investigates the degree to which mid and late-gestation MIA with R-848 impacts offspring development and anxiety-like behavior. Pregnant rat dams received vehicle (phosphate-buffered saline) or R-848 (1 mg/kg, s.c.) injections on gestation day (GD) 14 (mid-gestation) or GD18 (late gestation). Maternal body weight as well as offspring body weight, developmental milestones, and anxiety-like behavior were assessed. Although all dams gained weight throughout pregnancy, the R-848 dams from both injection days displayed pronounced weight fluctuations post-injection, with a trend toward attenuated weight gain in dams injected in late gestation. On postnatal day 21 (PND21), the R-848 dams injected on GD14 had significantly lower body weights (p=0.007) compared to the vehicle dams, whereas the body weights of the R-848 dams injected on GD18 did not differ significantly from the vehicles. Litter size, male-to-female ratio, and birth weight were also not affected by R-848. Semi-weekly offspring weights were not statistically different between any experimental groups by sex during any measured week in the mid-gestation-exposed cohort, but both male and female R-848-exposed offspring in the late-gestation exposure cohort displayed significantly decreased body weights at week 7 (males, p=0.0282 and females, p=0.0009). Eye opening, an important developmental milestone, was not different between the vehicle and R-848 pups regardless of the timing of exposure. Open field testing in the mid-gestation-exposed adult offspring revealed no significant locomotion differences or differences in time spent in the center zone. Open field testing in the late-gestation-exposed adult offspring also revealed no locomotion differences, however, the R-848-exposed female offspring spent markedly less time in the center zone than all other groups. These findings suggest that late gestation R-848 exposure results in attenuated maternal weight gain as well as increased anxiety-like behaviors in female offspring. Future exploration of pre-pubertal stages and assessments of autonomic regulation in offspring exposed to R-848 in late gestation will provide further insight into the long-term consequences of immune activation during pregnancy. NIH U54 MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Elevated circulating adiponectin levels do not prevent anxiety-like behavior in a PCOS-like mouse model

Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels of the adipocyte hormone adiponectin. Androgen exposure leads to anxiety-like behavior in female offspring while adiponectin is reported to be anxiolytic. Here we test the hypothesis that elevated adiponectin levels protect against the development of androgen-induced anxiety-like behavior. Pregnant mice overexpressing adiponectin (APNtg) and wildtypes were injected with vehicle or dihydrotestosterone to induce prenatal androgenization (PNA) in the offspring. Metabolic profiling and behavioral tests were performed in 4-month-old female offspring. PNA offspring spent more time in the closed arms of the elevated plus maze, indicating anxiety-like behavior. Intriguingly, neither maternal nor offspring adiponectin overexpression prevented an anxiety-like behavior in PNA-exposed offspring. However, adiponectin overexpression in dams had metabolic imprinting effects, shown as lower fat mass and glucose levels in their offspring. While serum adiponectin levels were elevated in APNtg mice, cerebrospinal fluid levels were similar between genotypes. Adiponectin overexpression improved metabolic functions but did not elicit anxiolytic effects in PNA-exposed offspring. These observations might be attributed to increased circulating but unchanged cerebrospinal fluid adiponectin levels in APNtg mice. Thus, increased adiponectin levels in the brain are likely needed to stimulate anxiolytic effects.

Prenatal Stress Induces Long-Term Behavioral Sex-Dependent Changes in Rats Offspring: the Role of the HPA Axis and Epigenetics.

Preclinical genetic studies have related stress early exposures with changes in gene regulatory mechanisms, including epigenetic alterations, such as modifications of DNA methylation, histone deacetylation, and histones acetylation. This study evaluates the effects of prenatal stress on the behavior, hypothalamus-pituitary-adrenal (HPA)-axis, and epigenetic parameters in stressed dams and their offspring. The rats were subjected to a protocol of chronic unpredictable mild stress on the fourteenth day of pregnancy until the birth of offspring. After birth, maternal care was evaluated for six days. Following weaning, the locomotor and depressive-like behaviors of the dams and their offspring (60 days old) were assessed. The HPA axis parameters were evaluated in serum from dams and offspring, and epigenetic parameters (histone acetyltransferase (HAT), histone deacetylase (HDAC), DNA methyltransferase (DNMT) activities, and the levels of histone H3 acetylated at lysine residue 9 (H3K9ac) and histone 3 acetylated at lysine residue 14 (H3K14ac)) were assessed in dams' and offspring' brains. Prenatal stress did not significantly influence maternal care; however, it induced manic behavior in female offspring. These behavioral alterations in the offspring were accompanied by hyperactivity of the HPA-axis, epigenetic adaptations in the activity of HDAC and DNMT, and acetylation in the histones H3K9 and H3K14. In addition, the prenatal stressed female offspring showed increased levels of ACTH compared to their male counterpart. Our findings reinforce the impact of prenatal stress on behavior, stress response, and epigenetic profile of offspring.

Remodulation Effect of Elateriospermum tapos Yoghurt on Metabolic Profile of Maternal Obesity Induced Cognitive Dysfunction and Anxiety-like Behavior in Female Offspring-An In Vivo Trial on Sprague Dawley Rats.

Pre-pregnancy weight gain induces dysregulation in the metabolic profile of the offspring, thereby serving as a key factor for cognitive decline and anxiety status in the offspring. However, early probiotic supplementation during the gestational period is linked with improved metabolic health. At the same time, a natural plant known as Elateriospermum tapos (E. tapos) is proven to improve cognition and modulate the stress hormone due to its high concentration of flavonoids. However, the effects of medicinal plant integrated probiotics in F1 generations warrants further investigation. Thus, this study aimed to study the effect of E. tapos yoghurt on the maternal obesity induced cognitive dysfunction and anxiety in female offspring. In this study, female Sprague Dawley rats were fed with normal chow (n = 8) or high fat diet (n = 40) across pre-pregnancy, gestation, and weaning. The treatment with different concentrations of E. tapos yoghurt (5, 50, and 500 mg/kg/day) were initiated in the obese dams upon post coitum day 0 up to postnatal day 21 (PND 21). Female offspring were weaned on PND 21 and body mass index, waist circumference, lee index, behavior, metabolic parameter, and antioxidant status were analyzed. The result shows that the female offspring of the 500 mg/kg E. tapos yoghurt supplemented group shows a decreased level of insulin, fasting blood glucose, cholesterol, triglycerides, LDL, low fat tissue mass with a high level of HDL, and an increased level of antioxidant status in the hypothalamus. The behavioral assessment proves that the female offspring of the 500 mg/kg E. tapos yoghurt supplemented group exhibits a high recognition index on novel object/place with low anxiety-like behavior in an open field test. In conclusion, our data signify the beneficial effect of early intervention in obese dams on the transgenerational impact on female offspring's metabolic profile, cognitive performance, and anxiety-like behavior.

Maternal Protein Restriction in Rats Alters Postnatal Growth and Brain Lipid Sensing in Female Offspring.

Perinatal nutrition is a key player in the susceptibility to developing metabolic diseases in adulthood, leading to the concept of "metabolic programming". The aim of this study was to assess the impact of maternal protein restriction during gestation and lactation on glucose homeostasis and eating behaviour in female offspring. Pregnant rats were fed a normal or protein-restricted (PR) diet and followed throughout gestation and lactation. Body weight, glucose homeostasis, and eating behaviour were evaluated in offspring, especially in females. Body weight gain was lower in PR dams during lactation only, despite different food and water intakes throughout gestation and lactation. Plasma concentration of leptin, adiponectin and triglycerides increased drastically before delivery in PR dams in relation to fat deposits. Although all pups had identical birth body weight, PR offspring body weight differed from control offspring around postnatal day 10 and remained lower until adulthood. Offspring glucose homeostasis was mildly impacted by maternal PR, although insulin secretion was reduced for PR rats at adulthood. Food intake, satiety response, and cerebral activation were examined after a lipid preload and demonstrated some differences between the two groups of rats. Maternal PR during gestation and lactation does induce extrauterine growth restriction, accompanied by alterations in maternal plasma leptin and adiponectin levels, which may be involved in programming the alterations in eating behaviour observed in females at adulthood.

Maternal immune activation attenuates cisplatin-induced fatigue-like behavior in female offspring

Maternal immune activation attenuates cisplatin-induced fatigue-like behavior in female offspring

Brief Maternal Separation Promotes Resilience to Anxiety-like and Depressive-like Behaviors in Female C57BL/6J Offspring with Imiquimod-Induced Psoriasis.

Background: Psoriasis is a common chronic inflammatory skin disease that often causes depression. Early life experience affects brain development and relates to depression. Whether the effect of different MS protocols in early life on anxiety-like and depressive-like behaviors in female offspring with imiquimod (IMQ)-induced psoriasis is unknown. Methods: C57BL/6J mice were subjected to no separation (NMS), brief MS (15 min/day, MS15) or long MS (180 min/day, MS180) from postpartum days (PPD) 1 to PPD21. Then, 5% imiquimod cream was applied for 8 days in adults. Behavioral tests, skin lesions and hippocampal protein expression were also assessed. Results: We found significant psoriasis-like skin lesions in female mice following IMQ application, and mice showed anxiety-like and depressive-like behaviors. Further, increased microglial activation and decreased expression of neuroplasticity were detected in mice following IMQ application. However, after MS15 in early life, mice showed decreased anxiety-like and depressive-like behaviors, indicating resilience. Further, inhibited hippocampal neuroinflammation and increased neuroplasticity were detected. Conclusions: Collectively, this study confirms that brief MS confers resilience to the behavior deficits in female offspring with IMQ-induced psoriasis and reverses the activation of neuroinflammation and the damage of neuroplasticity injury.

Gender differences in short- vs. long-term impact of maternal depression following pre-gestational chronic mild stress

Major Depressive Disorder (MDD) with Peripartum Onset was classified in 2013 by the Diagnostic and Statistical Manual, Fifth Edition (DMS-5) and approved in 2019 by the World Health Organization (WHO). These diagnostic revisions call for the development of new animal models of maternal depression, emphasizing the pregnancy period. We have recently described a novel rat model of maternal MDD with a Peripartum Onset. Exposure to pre-gestational chronic mild stress (CMS) with repeated restrain resulted in maternal depressive-like behavior and impacted offspring's neurodevelopment. The present study examined gender differences in short- vs. long-term neurodevelopmental impact of pre-gestational maternal stress. Stress response was assessed in Sprague Dawley CMS-exposed dams (n=7) by metabolic, hormonal, and behavioral changes and compared to controls dams (n=7). Short-term impact of maternal stress on offspring was examined in terms of metabolic, neurodevelopmental, and behavioral tests in male (n=40) and female (n=35) adolescent offspring on a postnatal day (PD) 48; the long-term impact was assessed in adult male (n=13) and female (n=12) offspring on PD 225. Brain tissue was collected from adolescent and adult offspring for biochemical analysis. Maternal stress was associated with decreased body weight and increased urinary corticosterone during the pre-pregnancy period, but depressive-like behavior was delayed until later in pregnancy. No significant neurodevelopmental changes in suckling male or female offspring derived from the stress-exposed dams were observed. However, adolescent male and female offspring of stress-exposed dams displayed an increased depressive-like behavior and gender-dependent increase in anxiety-like behavior in female offspring. These changes were associated with a brain-region-specific increase in brain-derived neurotrophic factor (BDNF) protein and BDNF receptor (TrkB) mRNA in males. Behavioral changes observed in the adolescents receded in adult male and female offspring. However, plasma BDNF was elevated in stress-exposed adult female offspring. These results suggest that pre-gestational maternal stress is associated with gender-dependent short- vs. long-term neurodevelopmental impact in the offspring. Presented data are of significant public health relevance, and there is an urgent need for further research to confirm these findings and probe the underlying mechanisms.

Maternal obesity impairs social behavior in female offspring by decreasing central estrogen function

Maternal obesity impairs social behavior in female offspring by decreasing central estrogen function

Excess Folic Acid Supplementation before and during Pregnancy and Lactation Alters Behaviors and Brain Gene Expression in Female Mouse Offspring.

Use of folic acid (FA) during early pregnancy protects against birth defects. However, excess FA has shown gender-specific neurodevelopmental toxicity. Previously, we fed the mice with 2.5 times the recommended amount of FA one week prior to mating and during the pregnancy and lactation periods, and detected the activated expression of Fos and related genes in the brains of weaning male offspring, as well as behavioral abnormalities in the adults. Here, we studied whether female offspring were affected by the same dosage of FA. An open field test, three-chamber social approach and social novelty test, an elevated plus-maze, rotarod test and the Morris water maze task were used to evaluate their behaviors. RNA sequencing was performed to identify differentially expressed genes in the brains. Quantitative real time-PCR (qRT-PCR) and Western blots were applied to verify the changes in gene expression. We found increased anxiety and impaired exploratory behavior, motor coordination and spatial memory in FA-exposed females. The brain transcriptome revealed 36 up-regulated and 79 down-regulated genes in their brains at weaning. The increase of Tlr1; Sult1a1; Tph2; Acacb; Etnppl; Angptl4 and Apold1, as well as a decrease of Ppara mRNA were confirmed by qRT-PCR. Among these genes; the mRNA levels of Etnppl; Angptl4 and Apold1 were increased in the both FA-exposed female and male brains. The elevation of Sult1a1 protein was confirmed by Western blots. Our data suggest that excess FA alteres brain gene expression and behaviors in female offspring, of which certain genes show apparent gender specificity.

Neurosteroid-based intervention using Ganaxolone and Emapunil for improving stress-induced myelination deficits and neurobehavioural disorders

BackgroundPrenatal stress is associated with long-term disturbances in white matter development and behaviour in children, such as attention deficit hyperactivity disorder (ADHD) and anxiety. Oligodendrocyte maturation and myelin formation is a tightly orchestrated process beginning during gestation, and therefore is very vulnerable to the effects of maternal prenatal stresses in mid-late pregnancy. The current study aimed to examine the effects of prenatal stress on components of the oligodendrocyte lineage to identify the key processes that are disrupted and to determine if postnatal therapies directed at ameliorating white matter deficits also improve behavioural outcomes. MethodsPregnant guinea pig dams were exposed to control-handling or prenatal stress with strobe light exposure for 2hrs/day on gestational age (GA) 50, 55, 60 and 65, and allowed to spontaneously deliver ~GA70. Pups were administered oral ganaxolone (5 mg/kg/day in 45% cyclodextrin) or the TSPO agonist, emapunil (XBD173; 0.3 mg/kg/day in 1% tragacanth gum) or vehicle, on postnatal days (PND) 1–7. Behavioural outcomes were assessed using open field and elevated plus maze testing on PND7 and PND27. Hippocampal samples were collected at PND30 to assess markers of oligodendrocyte development through assessment of total oligodendrocytes (OLIG2) and mature cells (myelin basic protein; MBP), and total neurons (NeuN) by immunostaining. Real-time PCR was conducted on hippocampal regions to assess markers of the oligodendrocyte lineage, markers of neurogenesis and components of the neurosteroidogenesis pathway. Plasma samples were collected for steroid quantification of cortisol, allopregnanolone, progesterone and testosterone by ELISA. ResultsPrenatal stress resulted in hyperactivity in male offspring, and anxiety-like behaviour in female offspring in the guinea pig at an age equivalent to late childhood. Postnatal ganaxolone and emapunil treatment after prenatal stress restored the behavioural phenotype to that of control in females only. The oligodendrocyte maturation lineage, translation of MBP mRNA-to-protein, and neurogenesis were disrupted in prenatally-stressed offspring, resulting in a decreased amount of mature myelin. Emapunil treatment restored mature myelin levels in both sexes, and reversed disruptions to the oligodendrocyte lineage in female offspring, an effect not seen with ganaxolone treatment. ConclusionThe marked and persisting behavioural and white matter perturbations observed in a clinically relevant guinea pig model of prenatal stress highlights the need for postnatal interventions that increase myelin repair and improve long-term outcomes. The effectiveness of emapunil treatment in restoring female offspring behaviour, and promoting maturation of myelin indicates that early therapeutic interventions can reverse the damaging effects of major stressful events in pregnancy. Further studies optimising target mechanisms and dosing are warranted.

The effects of perinatal fluoxetine exposure on emotionality behaviours and cortical and hippocampal glutamatergic receptors in female Sprague-Dawley and Wistar-Kyoto rats

RationaleThere is increasing concern regarding the use of selective serotonin reuptake inhibitors (SSRIs) in pregnancy. Animal studies repeatedly show increased anxiety- and depressive-like behaviours in offspring exposed perinatally to SSRIs, however much of this research is in male offspring. ObjectivesThe primary aim of this study was to investigate the effects of perinatal SSRI exposure on emotionality-related behaviours in female offspring and associated glutamatergic markers, in Sprague-Dawley (SD) rats and in the Wistar-Kyoto (WKY) rat model of depression. Secondly, we sought to investigate the glutamatergic profile of female WKY rats that may underlie their depressive- and anxiety-like phenotype. MethodsWKY and SD rat dams were treated with the SSRI, fluoxetine (FLX; 10 mg/kg/day), or vehicle, throughout gestation and lactation (5 weeks total). Female adolescent offspring underwent behaviour testing followed by quantitative immunoblot of glutamatergic markers in the prefrontal cortex and ventral hippocampus. ResultsNaïve female WKY offspring displayed an anxiety-like and depressive-like phenotype as well as reductions in NMDA and AMPA receptor subunits and PSD-95 in both ventral hippocampus and prefrontal cortex, compared to SD controls. Perinatal FLX treatment increased anxiety-like and forced swim immobility behaviours in SD offspring but did not influence behaviour in female WKY offspring using these tests. Perinatal FLX exposure did not influence NMDA or AMPA receptor subunit expression in female WKY or SD offspring; it did however have restricted effects on group I mGluR expression in SD and WKY offspring and reduce the glutamatergic synaptic scaffold, PSD-95. ConclusionThese findings suggest female offspring of the WKY strain display deficits in glutamatergic markers which may be related to their depressive- and anxiety-like phenotype. While FLX exposed SD offspring displayed increases in anxiety-like and depressive-like behaviours, further studies are needed to assess the potential impact of developmental FLX exposure on the behavioural phenotype of female WKY rats.

Maternal Diet Influences the Reinstatement of Cocaine-Seeking Behavior and the Expression of Melanocortin-4 Receptors in Female Offspring of Rats.

Recent studies have emphasized the role of the maternal diet in the development of mental disorders in offspring. Substance use disorder is a major global health and economic burden. Therefore, the search for predisposing factors for the development of this disease can contribute to reducing the health and social damage associated with addiction. In this study, we focused on the impact of the maternal diet on changes in melanocortin-4 (MC-4) receptors as well as on behavioral changes related to cocaine addiction. Rat dams consumed a high-fat diet (HFD), high-sugar diet (HSD, rich in sucrose), or mixed diet (MD) during pregnancy and lactation. Using an intravenous cocaine self-administration model, the susceptibility of female offspring to cocaine reward and cocaine-seeking propensities was evaluated. In addition, the level of MC-4 receptors in the rat brain structures related to cocaine reward and relapse was assessed. Modified maternal diets did not affect cocaine self-administration in offspring. However, the maternal HSD enhanced cocaine-seeking behavior in female offspring. In addition, we observed that the maternal HSD and MD led to increased expression of MC-4 receptors in the nucleus accumbens, while increased MC-4 receptor levels in the dorsal striatum were observed after exposure to the maternal HSD and HFD. Taken together, it can be concluded that a maternal HSD is an important factor that triggers cocaine-seeking behavior in female offspring and the expression of MC-4 receptors.

The effects of prenatal dexamethasone exposure and fructose challenge on pituitary-adrenocortical activity and anxiety-like behavior in female offspring

Prenatal glucocorticoid overexposure could largely influence pituitary-adrenal activity and anxiety-like behavior in offspring. Our aim was to study the possible potentiating effect of moderate dose of fructose – common ingredient of today’s diet – on prenatal glucocorticoid treatment-induced hypothalamo-pituitary-adrenal (HPA) axis changes. Pregnant female rats were treated with multiple dexamethasone (Dx) doses (3 x 0.5 mg/kg/b.m. Dx; 16th-18th gestational day). Half of female offspring from control and Dx treated dams were supplemented with 10% fructose solution, from weaning till adulthood. Immunohistochemistry, unbiased stereological evaluation and hormonal analysis are used to provide the morpho-functional state of pituitary and adrenal gland. Anxiety-like behavior was assessed using the light/dark box test and the elevated plus maze test. Prenatally Dx exposed females, with or without fructose consumption, had markedly reduced adrenocortical volume (p < 0.05) comparing to controls. Increased basal plasma ACTH level in these females (p < 0.05) maintained corticosterone concentration at control level produced by smaller adrenal glands. In parallel, anxiety-like behavior was shown by both tests used. In conclusion, prenatal Dx exposure cause negative psychophysiological outcome reflected in increased HPA axis activity and anxiety behavior in female offspring, while moderately increased fructose consumption failed to evoke any alteration or to potentiate effects of prenatal Dx exposure.

Prenatal Androgenization Induces Anxiety-Like Behavior in Female Rats, Associated with Reduction of Inhibitory Interneurons and Increased BDNF in Hippocampus and Cortex.

Anxiety is one of the most frequent psychiatric disorders. Despite the fact that most studies describe an anxiolytic effect of testosterone, hyperandrogenemia in mothers is assumed to be related to an increased risk of mood disorders in their offspring. An increasing body of scientific evidence suggests that an altered expression of interneuronal markers of the hippocampus may be the cause of anxiety. The aim of this study was to examine the influence of maternal hyperandrogenemia on behavioral parameters of anxiety-like behavior, neuropeptide Y (NPY) and parvalbumin (PV) expression in the hippocampus, and the level of the brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex. Pregnant female Wistar albino rats were treated with testosterone undecanoate on the 20th day of gestation. Anxiety-like behavior in adult female offspring was evaluated by the elevated plus maze test and the open field. The number of PV and NPY immunoreactive cells in the hippocampus was determined immunohistochemically. The level of BDNF expression in the hippocampus and cerebral cortex was analyzed with the Western blot test. Prenatal hyperandrogenization increased anxiety-like behavior in female offspring and decreased expression of NPY+ and PV+ in the CA1 region of the hippocampus as compared to the control group. BDNF expression in the hippocampus and cerebral cortex of prenatally androgenized female offspring was significantly increased in comparison with the controls. Prenatal hyperandrogenization may be the cause of anxiety-like behavior in female offspring. Decrease in NPY and PV expression in the hippocampus may explain the possible mechanism of hyperandrogenization induced anxiety.

Maternal Flavonoids Intake Reverts Depression-Like Behaviour in Rat Female Offspring.

Maternal hypercaloric exposure during pregnancy and lactation is a risk factor for developing diseases associated with inflammation such as obesity, diabetes and, neurological diseases in the offspring. Neuroinflammation might modulate neuronal activation and flavonoids are dietary compounds that have been proven to exert anti-inflammatory properties. Thus, the aim of the present study is to evaluate the effect of maternal supplementation with flavonoids (kaempferol-3-O-glucoside and narirutin) on the prevention of depression-like behaviour in the female offspring of dams fed with an obesogenic diet during the perinatal period. Maternal programming was induced by high fat (HFD), high sugar (HSD), or cafeteria diets exposure and depressive like-behaviour, referred to as swimming, climbing, and immobility events, was evaluated around postnatal day 56–60 before and after 30 mg/kg i.p. imipramine administration in the female offspring groups. Central inflammation was analyzed by measuring the TANK binding kinase 1 (TBK1) expression. We found that the offspring of mothers exposed to HSD programming failed to show the expected antidepressant effect of imipramine. Also, imipramine injection, to the offspring of mothers exposed to cafeteria diet, displayed a pro-depressive like-behaviour phenotype. However, dietary supplementation with flavonoids reverted the depression-like behaviour in the female offspring. Finally, we found that HSD programming increases the TBK1 inflammatory protein marker in the hippocampus. Our data suggest that maternal HSD programming disrupts the antidepressant effect of imipramine whereas cafeteria diet exposure leads to depressive-like behaviour in female offspring, which is reverted by maternal flavonoid supplementation.

Maternal modulation of paternal effects on offspring development.

The paternal transmission of environmentally induced phenotypes across generations has been reported to occur following a number of qualitatively different exposures and appear to be driven, at least in part, by epigenetic factors that are inherited via the sperm. However, previous studies of paternal germline transmission have not addressed the role of mothers in the propagation of paternal effects to offspring. We hypothesized that paternal exposure to nutritional restriction would impact male mate quality and subsequent maternal reproductive investment with consequences for the transmission of paternal germline effects. In the current report, using embryo transfer in mice, we demonstrate that sperm factors in adult food restricted males can influence growth rate, hypothalamic gene expression and behaviour in female offspring. However, under natural mating conditions females mated with food restricted males show increased pre- and postnatal care, and phenotypic outcomes observed during embryo transfer conditions are absent or reversed. We demonstrate that these compensatory changes in maternal investment are associated with a reduced mate preference for food restricted males and elevated gene expression within the maternal hypothalamus. Therefore, paternal experience can influence offspring development via germline inheritance, but mothers can serve as a modulating factor in determining the impact of paternal influences on offspring development.

Maternal care and affective behavior in female offspring: Implication of the neurosteroid/GABAergic system

In female rats, the proestrus phase of the estrous cycle is associated with decreased levels of anxiety-like and depressive-like behavior relative to the metestrus phase. Progesterone likely modulate these behaviors, in part through the influence of its metabolite, allopregnanolone (THP) on hippocampal GABAAR subunit expression. As natural variations in maternal care have been found to influence both progesterone levels at proestrus and anxiety-like behavior in female offspring, we sought to investigate the importance of maternal care and the estrous cycle on affective behavior in female rats that had received Low or High levels of licking/grooming (LG) during early life. Subjects were tested for anxiety-like behavior in the elevated plus maze at proestrus or metestrus or for estrous cycle-dependent changes in depressive-like anhedonic behavior with a saccharin preference test. GABAAR subunit expression, and THP levels in the dorsal hippocampus and in plasma were also evaluated. Estrous cycle phase influenced saccharine preference and hippocampal THP level in both phenotypes. Low LG animals showed higher levels of hedonic behavior and anxiety-like behavior, irrespective of estrous cycle phase, as well as lower THP levels within the dorsal hippocampus when compared to High LG animals. Only High LG animals showed positive correlations between hippocampal THP levels and GABAAR subunit expression, suggesting a relative insensitivity to THP’s modulation of these receptor subunits in Low LG offspring. These findings suggest that natural variations in maternal care influence anxiety-like and hedonic behavior through the modulation of the neurosteroid/GABAergic system.

Enhanced anxiety in the male offspring of sires that self-administered cocaine.

We previously showed that paternal cocaine exposure reduced the reinforcing efficacy of cocaine in male offspring. Here, we sought to determine whether paternal cocaine experience could also influence anxiety levels in offspring. Male rats were allowed to self-administer cocaine (controls received saline passively) for 60 days and then were bred with naïve females. Measures of anxiety and cocaine-induced anxiogenic effects were assessed in the adult offspring. Cocaine-sired male offspring exhibited increased anxiety-like behaviors, as measured using the novelty-induced hypophagia and defensive burying tasks, relative to saline-sired males. In contrast, sire cocaine experience had no effect on anxiety-like behaviors in female offspring. When challenged with an anxiogenic (but not anorectic) dose of cocaine (2.5 mg/kg, i.p.), anxiety-like behavior was enhanced in all animals to an equal degree regardless of sire drug experience. Since anxiety and depression are often co-morbid, we also assessed measures of depressive-like behavior. Sire cocaine experience had no effect on depression-like behaviors, as measured by the forced swim task, among male offspring. In a separate group of naïve littermates, select neuronal correlates of anxiety were measured. Male offspring of cocaine-experienced sires showed increased mRNA and protein expression of corticotropin-releasing factor receptor 2 in the hippocampus. Together, these results indicate that cocaine-experienced sires produce male progeny that have increased baseline anxiety, which is unaltered by subsequent cocaine exposure.

The impact of pre-natal stress on offspring development in pigs

SUMMARYIn farm animals, restricted housing conditions or inadequate management practices during gestation may be potential stressors for the mother, with possible consequences on the growth, vitality, health and welfare of the dam and its offspring, and thus can have economic as well as ethical implications. The current review summarizes data from studies in pigs on the impact of maternal stress during gestation on the litter characteristics and phenotypic traits of offspring. The outcomes from the different experimental models using either maternal stress paradigms or artificially increased maternal cortisol are presented, and possible reasons for the consistent or divergent results are discussed. Maternal stress models are of particular importance, because social stress, restraint, rough handling and heat or cold stress are of practical relevance during housing of pregnant sows, whereas in other models the specific role of maternal cortisol as a mediator for pre-natal stress is studied. The data reveal that pre-natal stress in pigs can impair growth and modify the immune function, stress reactivity and behaviour of offspring. There is evidence that the materno-foetal cortisol regulation is a major determinant of the alterations in offspring. Neuroendocrine and behavioural data in the offspring indicate that pre-natally stressed pigs can express a modified phenotype characterized by increased reactivity of the hypothalamic–pituitary–adrenal axis, altered emotionality, more fearfulness in a novel environment and disturbed social and maternal behaviour. Further research is needed and should focus on the long-term consequences on immune function, reproductive traits and maternal behaviour in female offspring used as breeding animals.